{"gene":"NDC1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1993,"finding":"Yeast Ndc1p is required for spindle pole body (SPB) duplication, specifically for insertion of the nascent SPB into the nuclear envelope. The protein encodes 656 amino acids with six or seven putative transmembrane domains and localizes to the nuclear envelope by immunofluorescence. Order-of-function experiments place NDC1 function in G1 after alpha-factor arrest but before cdc34 arrest.","method":"Electron microscopy of temperature-sensitive ndc1-1 mutants, immunofluorescence localization, genetic order-of-function experiments, molecular cloning","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (EM, immunofluorescence, genetic epistasis) in a foundational study, replicated in subsequent work","pmids":["8349727"],"is_preprint":false},{"year":1999,"finding":"NDC1 is haploinsufficient in diploid yeast; a single chromosomal copy cannot support viability, leading to aneuploidy. Overexpression of NDC1 causes SPB duplication defects, monopolar spindles, and increase-in-ploidy phenotypes, demonstrating that both increased and decreased NDC1 dosage disrupt SPB duplication.","method":"Yeast genetic dosage experiments, flow cytometry, microscopy of spindle morphology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic dosage analysis with multiple phenotypic readouts in a single lab study","pmids":["10468586"],"is_preprint":false},{"year":2004,"finding":"Yeast Ndc1p is required for NPC assembly in addition to SPB duplication. The ndc1-39 temperature-sensitive allele blocks SPB insertion into the nuclear envelope and fails to incorporate the nucleoporin Nup49p into NPCs. Genetic interaction (enhanced growth defects) between ndc1-39 and nic96-1 NPC assembly mutant places Ndc1p in the NPC assembly pathway.","method":"Temperature-sensitive allele analysis, genetic epistasis (double mutant), nucleoporin incorporation assay, nuclear protein import assay","journal":"Eukaryotic cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis and direct nucleoporin incorporation assay, single lab","pmids":["15075274"],"is_preprint":false},{"year":2006,"finding":"Vertebrate NDC1 is a transmembrane nucleoporin required for NPC and nuclear envelope assembly. RNAi depletion in HeLa cells interferes with assembly of FG-repeat nucleoporins into NPCs. NDC1 interacts directly with Nup53 in vitro, suggesting it links the NE membrane to soluble nucleoporins to anchor the NPC in the membrane.","method":"RNAi knockdown, biochemical depletion in Xenopus in vitro NE assembly, in vitro binding assay (NDC1–Nup53 interaction)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi phenotype plus in vitro NE assembly plus direct binding assay, replicated across vertebrate systems and consistent with companion paper","pmids":["16600873"],"is_preprint":false},{"year":2006,"finding":"Human NDC1 (hNDC1) likely possesses six transmembrane segments and is located at the nuclear pore wall in mammals, frogs, insects, and nematodes. Depletion of hNDC1 from HeLa cells interferes with assembly of FG-repeat nucleoporins into NPCs. Loss of NDC1 function in C. elegans causes severe NPC defects and high larval/embryonic mortality, but homozygous NDC1-deficient worms can be propagated, indicating NDC1 is not absolutely essential.","method":"RNAi depletion, immunofluorescence, electron microscopy, C. elegans genetics","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods across multiple organisms, independent lab confirming companion study","pmids":["16702233"],"is_preprint":false},{"year":2006,"finding":"The overall topology of Ndc1p is conserved from yeast to humans: six transmembrane segments in the N-terminal half, a large soluble C-terminal half (~300 aa) with the N- and C-termini exposed to the cytoplasm. Limited proteolysis of yeast Ndc1p in cellular membranes confirms the cytoplasmic orientation of its C-terminus. The human homologue (NET3/NDC1) contains three FG repeats in the C-terminus characteristic of nucleoporins.","method":"Limited proteolysis in cellular membranes, topology prediction, sequence analysis","journal":"The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — limited proteolysis experiment establishes C-terminal topology but performed in single lab with one method","pmids":["16779818"],"is_preprint":false},{"year":2008,"finding":"Recruitment of vesicles containing the integral membrane nucleoporins POM121 and NDC1 to the forming nucleus depends on chromatin-bound ELYS/Nup107-160 complex, placing NDC1-containing vesicle recruitment downstream of ELYS and the Nup107-160 complex in the nuclear pore assembly pathway.","method":"Xenopus in vitro nuclear assembly, antibody inhibition, immunofluorescence, DNA-binding antibiotic competition assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution with inhibition experiments establishing pathway order, single lab","pmids":["18596237"],"is_preprint":false},{"year":2009,"finding":"Yeast Ndc1 forms a distinct complex with transmembrane proteins Pom152 and Pom34, and two alternative complexes with soluble nucleoporins Nup53 and Nup59 (which in turn bind Nup170 and Nup157). Disruption of both groups of Ndc1 interactions causes defects in Ndc1 targeting and NPC structure with significant pore dilation. Depletion of Pom34 in cells lacking NUP53 and NUP59 blocks new NPC assembly.","method":"Co-immunoprecipitation, genetic double/triple mutant analysis, photoconvertible fluorescent protein fusions to track new NPC assembly, electron microscopy","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, genetic epistasis, live-imaging of NPC assembly, and EM structural analysis in one study","pmids":["19414609"],"is_preprint":false},{"year":2009,"finding":"NDC1 is required for anchoring ALADIN at the NPC; siRNA depletion of NDC1 (but not GP210 or POM121) causes mislocalization of GFP-ALADIN. Conversely, depletion of ALADIN also leads to loss of NDC1 at the NPC. Direct association between NDC1 and ALADIN was demonstrated by FRET measurements.","method":"siRNA knockdown, GFP-ALADIN localization by fluorescence microscopy, FRET measurements","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with localization readout plus FRET for direct association, two orthogonal methods in single lab","pmids":["19782045"],"is_preprint":false},{"year":2009,"finding":"NDC1 directly interacts with nucleoporin ALADIN, and this interaction is required for targeting ALADIN to NPCs. NDC1 is also required for selective nuclear import.","method":"Co-immunoprecipitation, siRNA knockdown with localization readout, nuclear import assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding shown by Co-IP, functional consequence demonstrated by siRNA, consistent with companion paper","pmids":["19703420"],"is_preprint":false},{"year":2012,"finding":"Ndc1 physically interacts with the membrane-shaping proteins Rtn1 and Yop1 in yeast. Overexpression of NDC1 (but not other SPB insertion factors) rescues both SPB and NPC defects in rtn1Δ yop1Δ cells, suggesting Ndc1 is a common essential component competed for between NPC and SPB biogenesis pathways.","method":"Co-immunoprecipitation, genetic rescue by overexpression, electron microscopy, spindle orientation assay","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — physical interaction by Co-IP plus genetic rescue with pathway specificity, single lab","pmids":["22798490"],"is_preprint":false},{"year":2013,"finding":"The interaction between Nup53 and the integral membrane protein Ndc1 is essential for vertebrate NPC assembly. The Ndc1-binding site on Nup53 overlaps with a membrane-bending region, and Ndc1 binding modulates Nup53's membrane-deforming activity. Nup53–Nup155 interaction is also critical for NPC formation as the main determinant of Nup155 recruitment to the assembling pore.","method":"In vitro binding assays, mutagenesis of Nup53 interaction domains, Xenopus in vitro NE assembly, depletion/rescue experiments","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding with mutagenesis, in vitro assembly reconstitution, multiple orthogonal methods in single lab","pmids":["24363447"],"is_preprint":false},{"year":2013,"finding":"A mutation in mouse Tmem48 (NDC1) causes gametogenesis defects with meiotic arrest at pachytene stage due to defective chromosome synapsis, and skeletal malformations with fused vertebrae and ribs. TMEM48 is specifically expressed in germ cells. Transgenic rescue with wild-type Tmem48 fully rescues phenotypes, confirming causality.","method":"Mouse genetics (positional cloning, whole exome sequencing), transgenic rescue, histology, immunocytochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — positional cloning with transgenic rescue establishing causality, multiple phenotypic readouts","pmids":["24045954"],"is_preprint":false},{"year":2014,"finding":"Yeast Ndc1 interacts with the SUN domain-containing protein Mps3 at the nuclear envelope, as shown by fluorescence cross-correlation spectroscopy in live cells. The ndc1-L562S allele, unable to associate with Mps3, is lethal due to SPB duplication defects. Deletion of POM152 fully suppresses the growth and Mps3-binding defect of ndc1-L562S, suggesting Ndc1-Mps3 interaction controls distribution of Ndc1 between NPC and SPB.","method":"Fluorescence cross-correlation spectroscopy (FCCS) in live cells, genetic allele analysis, suppressor genetics","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FCCS for direct interaction in live cells plus genetic suppression analysis, single lab","pmids":["24515347"],"is_preprint":false},{"year":2016,"finding":"NDC1 forms a complex with SEPTIN12 (SEPT12) in male germ cells. NDC1 overexpression restricts SEPT12 localization to the nucleus and represses SEPT12 filament formation. In sperm with mutated SEPT12, NDC1 disperses from the sperm neck to the manchette region and annulus. SEPT12-NDC1 complexes are required for normal spermiogenesis and sperm morphology.","method":"Co-immunoprecipitation, yeast 2-hybrid, immunofluorescence co-localization, overexpression experiments in germ cell lines, mouse knockout/knock-in models","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus yeast 2-hybrid for interaction, multiple functional readouts in mouse models, single lab","pmids":["27854341"],"is_preprint":false},{"year":2022,"finding":"In C. elegans, Ndc1 determines NPC density at the reforming nuclear envelope. Loss of ndc1 results in faster turnover of the outer scaffold nucleoporin Nup160 at the NE (measured by FRAP-like photoconversion). NE formation fails in the absence of both Ndc1 and Nup53, indicating partially redundant roles. Upregulation of membrane synthesis restores nuclear growth after ndc1 loss but not after nup53 loss, demonstrating that membrane biogenesis can be decoupled from Ndc1-mediated NPC assembly.","method":"3D-EM tomography, photoconvertible fluorescent protein fusions for nucleoporin turnover, RNAi depletion, genetic double-mutant analysis, membrane synthesis manipulation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — EM tomography, live imaging with photoconversion, multiple genetic combinations, and orthogonal membrane manipulation in one rigorous study","pmids":["35852146"],"is_preprint":false},{"year":2023,"finding":"ARRDC5 affects NDC1 localization during spermatogenesis by influencing SEC22A-mediated vesicle trafficking and transport of NDC1 and SUN5 to the head-tail coupling apparatus. In Arrdc5 knockout mice, sperm show bent-head defects and reduced motility due to failure of proper head-tail attachment.","method":"Mouse knockout model, mass spectrometry identification of NDC1 as ARRDC5 interactor, co-localization studies, intracytoplasmic sperm injection rescue","journal":"Development (Cambridge, England)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mass spectrometry identification plus KO phenotype, but the mechanism specific to NDC1 function is inferred rather than directly tested","pmids":["37997706"],"is_preprint":false},{"year":2024,"finding":"NDC1 activates PI3K/AKT signaling in hepatocellular carcinoma cells by interacting with BCAP31. Co-immunoprecipitation and mass spectrometry confirmed the NDC1–BCAP31 interaction.","method":"Co-immunoprecipitation, mass spectrometry, overexpression and knockdown in HCC cell lines, mouse xenograft","journal":"Journal of biochemical and molecular toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/MS interaction without mechanistic dissection of how NDC1–BCAP31 activates PI3K/AKT, single lab","pmids":["38348718"],"is_preprint":false},{"year":2024,"finding":"Biallelic NDC1 in-frame deletions or missense variants affecting amino acids required for ALADIN binding cause decreased recruitment of ALADIN to the nuclear envelope and decreased post-mitotic NPC insertion in patient-derived skin fibroblasts, resulting in polyneuropathy and a triple A-like syndrome without adrenal insufficiency.","method":"Diagnostic exome/RNA sequencing, skin fibroblast functional assays (ALADIN localization, NPC insertion assay), clinical correlation","journal":"HGG advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cell functional assays with direct NPC insertion measurement and ALADIN localization, consistent with prior mechanistic studies","pmids":["39003500"],"is_preprint":false}],"current_model":"NDC1 (TMEM48/NET3) is a conserved integral membrane nucleoporin with six transmembrane segments whose cytoplasmic C-terminal domain interacts with multiple soluble nucleoporins (Nup53, Nup59, and ALADIN) and transmembrane proteins (Pom152, Pom34, Mps3, Rtn1/Yop1), anchoring nuclear pore complexes (and in yeast, spindle pole bodies) in the nuclear envelope by linking the NE membrane to the soluble NPC scaffold; its membrane-deforming partner Nup53 binding modulates membrane curvature during pore biogenesis, and it controls NPC density by stabilizing outer scaffold nucleoporins at the NE, with loss-of-function causing NPC assembly defects, gametogenesis failure, and (in humans) a triple A-like neuropathy via failure to recruit ALADIN to NPCs."},"narrative":{"mechanistic_narrative":"NDC1 (TMEM48/NET3) is a conserved integral membrane nucleoporin that anchors nuclear pore complexes (NPCs) in the nuclear envelope by linking the NE membrane to the soluble NPC scaffold [PMID:16600873, PMID:16702233]. The protein adopts a conserved topology of six transmembrane segments in its N-terminal half and a large cytoplasmically exposed C-terminal domain that mediates its protein interactions [PMID:16779818]. During NPC biogenesis, NDC1-containing membrane vesicles are recruited downstream of the chromatin-bound ELYS/Nup107-160 complex [PMID:18596237], and NDC1 directly binds the soluble nucleoporin Nup53; because the Ndc1-binding site on Nup53 overlaps a membrane-bending region, this interaction modulates Nup53's membrane-deforming activity during pore formation and is essential for vertebrate NPC assembly [PMID:16600873, PMID:24363447]. In yeast, Ndc1 partitions among distinct assemblies—a transmembrane complex with Pom152 and Pom34 and alternative complexes with the soluble nucleoporins Nup53/Nup59—and disrupting both interaction groups mislocalizes Ndc1 and dilates pores [PMID:19414609]. NDC1 sets NPC density by stabilizing outer-scaffold nucleoporins at the NE, acting partially redundantly with Nup53 in nuclear envelope formation; membrane biogenesis can be decoupled from Ndc1-dependent NPC assembly [PMID:35852146]. NDC1 also recruits the nucleoporin ALADIN to the NPC through direct interaction, and the two depend on each other for NPC localization [PMID:19782045, PMID:19703420]. In yeast the same protein is required for insertion of the duplicating spindle pole body into the nuclear envelope, a function competed for with NPC biogenesis and governed by interactions with the membrane-shaping proteins Rtn1/Yop1 and the SUN-domain protein Mps3 [PMID:8349727, PMID:22798490, PMID:24515347]. Loss-of-function disrupts gametogenesis: mouse Tmem48 mutation causes pachytene meiotic arrest from defective chromosome synapsis [PMID:24045954], and NDC1 forms a germ-cell complex with SEPTIN12 required for normal spermiogenesis [PMID:27854341]. In humans, biallelic NDC1 variants that impair ALADIN binding reduce ALADIN recruitment and post-mitotic NPC insertion, causing a triple A-like polyneuropathy syndrome [PMID:39003500].","teleology":[{"year":1993,"claim":"Established the founding function of Ndc1 by showing it is required for insertion of the duplicating spindle pole body into the nuclear envelope, defining an NE-resident factor acting in G1.","evidence":"EM, immunofluorescence, and genetic order-of-function analysis of temperature-sensitive ndc1 mutants in yeast","pmids":["8349727"],"confidence":"High","gaps":["Did not identify molecular partners mediating SPB insertion","Did not connect Ndc1 to NPC assembly"]},{"year":1999,"claim":"Showed that NDC1 dosage is tightly constrained—both haploinsufficiency and overexpression disrupt SPB duplication—indicating it is a stoichiometry-sensitive component.","evidence":"Yeast genetic dosage experiments with flow cytometry and spindle morphology readouts","pmids":["10468586"],"confidence":"Medium","gaps":["Mechanism linking dosage to SPB defects not resolved","Did not address NPC role"]},{"year":2004,"claim":"Extended Ndc1 function beyond the SPB to NPC assembly, placing it in the NPC assembly pathway via nucleoporin incorporation and genetic interaction.","evidence":"Temperature-sensitive allele analysis, genetic epistasis with nic96-1, and nucleoporin incorporation assays in yeast","pmids":["15075274"],"confidence":"Medium","gaps":["Did not define direct binding partners","Mechanism of nucleoporin incorporation unresolved"]},{"year":2006,"claim":"Defined vertebrate NDC1 as a transmembrane nucleoporin required for NPC/NE assembly that links the NE membrane to soluble nucleoporins through a direct Nup53 interaction, and established conserved six-TM topology with a cytoplasmic C-terminus.","evidence":"RNAi in HeLa, Xenopus in vitro NE assembly, in vitro Nup53 binding, EM across multiple organisms, and limited proteolysis topology mapping","pmids":["16600873","16702233","16779818"],"confidence":"High","gaps":["Did not establish how Nup53 binding affects membrane shape","C. elegans data showed it is not absolutely essential, leaving redundancy unexplained"]},{"year":2008,"claim":"Ordered NDC1 vesicle recruitment within the assembly pathway, showing it depends on chromatin-bound ELYS/Nup107-160.","evidence":"Xenopus in vitro nuclear assembly with antibody inhibition and DNA-binding competition assays","pmids":["18596237"],"confidence":"Medium","gaps":["Did not identify the receptor coupling vesicles to the ELYS complex","Co-recruited POM121 vs NDC1 roles not separated"]},{"year":2009,"claim":"Mapped Ndc1 into discrete interaction modules—transmembrane (Pom152/Pom34) and soluble nucleoporin (Nup53/Nup59)—required for targeting and pore integrity, and identified ALADIN as an NDC1-dependent NPC partner.","evidence":"Reciprocal co-IP, genetic double/triple mutants, photoconvertible NPC-assembly imaging and EM in yeast; siRNA, FRET and co-IP for NDC1-ALADIN in human cells","pmids":["19414609","19782045","19703420"],"confidence":"High","gaps":["Structural basis of module partitioning not resolved","How ALADIN recruitment relates to NPC scaffold assembly unclear"]},{"year":2012,"claim":"Identified Ndc1 as a limiting factor shared between NPC and SPB biogenesis through interaction with membrane-shaping Rtn1/Yop1.","evidence":"Co-IP, genetic rescue by NDC1 overexpression, EM, and spindle orientation assays in yeast","pmids":["22798490"],"confidence":"Medium","gaps":["Did not quantify the competitive partitioning mechanism","Specificity of Rtn1/Yop1 effects on each pathway unresolved"]},{"year":2013,"claim":"Established the molecular logic of NDC1-Nup53 coupling—Ndc1 binds a Nup53 membrane-bending region and modulates its membrane-deforming activity—and showed Tmem48 mutation causes gametogenesis and skeletal defects in mouse with rescue confirming causality.","evidence":"In vitro binding with Nup53 mutagenesis and Xenopus NE assembly; mouse positional cloning/exome sequencing with transgenic rescue and histology","pmids":["24363447","24045954"],"confidence":"High","gaps":["Structural details of curvature modulation not resolved","Mechanism linking NPC defects to synapsis failure not defined"]},{"year":2014,"claim":"Showed an Ndc1-Mps3 (SUN-domain) interaction at the NE governs distribution of Ndc1 between NPC and SPB, with Pom152 deletion suppressing the binding-deficient allele.","evidence":"Fluorescence cross-correlation spectroscopy in live yeast, allele analysis, and suppressor genetics","pmids":["24515347"],"confidence":"Medium","gaps":["Did not resolve how partitioning is regulated through the cell cycle","Direct Mps3-binding interface not mapped structurally"]},{"year":2016,"claim":"Identified an NDC1-SEPTIN12 germ-cell complex controlling SEPT12 localization and required for normal spermiogenesis, extending NDC1's roles into sperm morphogenesis.","evidence":"Co-IP, yeast two-hybrid, immunofluorescence, overexpression in germ cell lines, and mouse knockout/knock-in models","pmids":["27854341"],"confidence":"Medium","gaps":["Whether SEPT12 interaction is NPC-related or independent unresolved","Direct binding interface not mapped"]},{"year":2022,"claim":"Defined NDC1 as a determinant of NPC density that stabilizes outer-scaffold nucleoporins and acts partially redundantly with Nup53, and decoupled membrane biogenesis from Ndc1-mediated NPC assembly.","evidence":"3D-EM tomography, photoconversion nucleoporin turnover, RNAi, double-mutant analysis and membrane-synthesis manipulation in C. elegans","pmids":["35852146"],"confidence":"High","gaps":["Molecular basis of scaffold stabilization not resolved","How redundancy with Nup53 is partitioned mechanistically unclear"]},{"year":2024,"claim":"Linked NDC1 to human disease by showing biallelic variants impairing ALADIN binding reduce ALADIN recruitment and post-mitotic NPC insertion, causing a triple A-like polyneuropathy.","evidence":"Diagnostic exome/RNA sequencing and patient-derived fibroblast functional assays for ALADIN localization and NPC insertion","pmids":["39003500"],"confidence":"Medium","gaps":["Tissue-specificity of the neuropathy phenotype not explained","Why adrenal insufficiency is absent unlike classical triple A unresolved"]},{"year":null,"claim":"How NDC1's NE/NPC scaffolding function relates to its reported roles in cancer signaling (BCAP31/PI3K-AKT) and to vesicle-trafficking factors (ARRDC5/SEC22A) in spermatogenesis remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["NDC1-BCAP31 mechanism activating PI3K/AKT not dissected","ARRDC5/SEC22A link to NDC1 inferred rather than directly tested","No structural model of the full NDC1 interactome"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,4,5,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,8,9,11]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,4,5,15]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,13]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[9,18]}],"complexes":["NPC (nuclear pore complex)","spindle pole body (yeast)","Ndc1-Pom152-Pom34 complex","NDC1-SEPTIN12 complex"],"partners":["NUP53","ALADIN","POM152","POM34","RTN1","MPS3","SEPT12"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BTX1","full_name":"Nucleoporin NDC1","aliases":["Transmembrane protein 48"],"length_aa":674,"mass_kda":76.3,"function":"Component of the nuclear pore complex (NPC), which plays a key role in de novo assembly and insertion of NPC in the nuclear envelope. Required for NPC and nuclear envelope assembly, possibly by forming a link between the nuclear envelope membrane and soluble nucleoporins, thereby anchoring the NPC in the membrane","subcellular_location":"Nucleus, nuclear pore complex; Nucleus membrane","url":"https://www.uniprot.org/uniprotkb/Q9BTX1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NDC1","classification":"Common Essential","n_dependent_lines":802,"n_total_lines":1208,"dependency_fraction":0.6639072847682119},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"COPA","stoichiometry":0.2},{"gene":"COPB2","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"YIPF5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NDC1","total_profiled":1310},"omim":[{"mim_id":"621328","title":"NEURODEVELOPMENTAL DISORDER WITH ACHALASIA, POLYNEUROPATHY, AND ALACRIMA; NEDAPA","url":"https://www.omim.org/entry/621328"},{"mim_id":"620944","title":"ARRESTIN DOMAIN-CONTAINING PROTEIN 5; ARRDC5","url":"https://www.omim.org/entry/620944"},{"mim_id":"613220","title":"TRANSMEMBRANE PROTEIN 18; TMEM18","url":"https://www.omim.org/entry/613220"},{"mim_id":"610115","title":"NDC1 TRANSMEMBRANE NUCLEOPORIN; NDC1","url":"https://www.omim.org/entry/610115"},{"mim_id":"608140","title":"NUCLEOPORIN, 35-KD; NUP35","url":"https://www.omim.org/entry/608140"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear membrane","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Actin filaments","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NDC1"},"hgnc":{"alias_symbol":["FLJ10407","NET3"],"prev_symbol":["TMEM48"]},"alphafold":{"accession":"Q9BTX1","domains":[{"cath_id":"-","chopping":"21-149_159-297","consensus_level":"high","plddt":90.0224,"start":21,"end":297},{"cath_id":"-","chopping":"315-390_548-672","consensus_level":"high","plddt":88.4656,"start":315,"end":672}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BTX1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BTX1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BTX1-F1-predicted_aligned_error_v6.png","plddt_mean":75.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NDC1","jax_strain_url":"https://www.jax.org/strain/search?query=NDC1"},"sequence":{"accession":"Q9BTX1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BTX1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BTX1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BTX1"}},"corpus_meta":[{"pmid":"16600873","id":"PMC_16600873","title":"The conserved transmembrane nucleoporin NDC1 is required for nuclear pore complex assembly in vertebrate cells.","date":"2006","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/16600873","citation_count":184,"is_preprint":false},{"pmid":"16702233","id":"PMC_16702233","title":"NDC1: a crucial membrane-integral nucleoporin of metazoan nuclear pore complexes.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16702233","citation_count":139,"is_preprint":false},{"pmid":"18596237","id":"PMC_18596237","title":"Capture of AT-rich chromatin by ELYS recruits POM121 and NDC1 to initiate nuclear pore assembly.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18596237","citation_count":134,"is_preprint":false},{"pmid":"8349727","id":"PMC_8349727","title":"NDC1: a nuclear periphery component required for yeast spindle pole body duplication.","date":"1993","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8349727","citation_count":126,"is_preprint":false},{"pmid":"19414609","id":"PMC_19414609","title":"Role of the Ndc1 interaction network in yeast nuclear pore complex assembly and maintenance.","date":"2009","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19414609","citation_count":115,"is_preprint":false},{"pmid":"24363447","id":"PMC_24363447","title":"Interaction of Nup53 with Ndc1 and Nup155 is required for nuclear pore complex assembly.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/24363447","citation_count":64,"is_preprint":false},{"pmid":"15075274","id":"PMC_15075274","title":"A novel allele of Saccharomyces cerevisiae NDC1 reveals a potential role for the spindle pole body component Ndc1p in nuclear pore assembly.","date":"2004","source":"Eukaryotic 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polyploidy.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10468586","citation_count":44,"is_preprint":false},{"pmid":"24515347","id":"PMC_24515347","title":"The SUN protein Mps3 controls Ndc1 distribution and function on the nuclear membrane.","date":"2014","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24515347","citation_count":39,"is_preprint":false},{"pmid":"19782045","id":"PMC_19782045","title":"The nuclear pore complex protein ALADIN is anchored via NDC1 but not via POM121 and GP210 in the nuclear envelope.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19782045","citation_count":34,"is_preprint":false},{"pmid":"19703420","id":"PMC_19703420","title":"The transmembrane nucleoporin NDC1 is required for targeting of ALADIN to nuclear pore complexes.","date":"2009","source":"Biochemical 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The protein encodes 656 amino acids with six or seven putative transmembrane domains and localizes to the nuclear envelope by immunofluorescence. Order-of-function experiments place NDC1 function in G1 after alpha-factor arrest but before cdc34 arrest.\",\n      \"method\": \"Electron microscopy of temperature-sensitive ndc1-1 mutants, immunofluorescence localization, genetic order-of-function experiments, molecular cloning\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EM, immunofluorescence, genetic epistasis) in a foundational study, replicated in subsequent work\",\n      \"pmids\": [\"8349727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"NDC1 is haploinsufficient in diploid yeast; a single chromosomal copy cannot support viability, leading to aneuploidy. Overexpression of NDC1 causes SPB duplication defects, monopolar spindles, and increase-in-ploidy phenotypes, demonstrating that both increased and decreased NDC1 dosage disrupt SPB duplication.\",\n      \"method\": \"Yeast genetic dosage experiments, flow cytometry, microscopy of spindle morphology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic dosage analysis with multiple phenotypic readouts in a single lab study\",\n      \"pmids\": [\"10468586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Yeast Ndc1p is required for NPC assembly in addition to SPB duplication. The ndc1-39 temperature-sensitive allele blocks SPB insertion into the nuclear envelope and fails to incorporate the nucleoporin Nup49p into NPCs. Genetic interaction (enhanced growth defects) between ndc1-39 and nic96-1 NPC assembly mutant places Ndc1p in the NPC assembly pathway.\",\n      \"method\": \"Temperature-sensitive allele analysis, genetic epistasis (double mutant), nucleoporin incorporation assay, nuclear protein import assay\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis and direct nucleoporin incorporation assay, single lab\",\n      \"pmids\": [\"15075274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Vertebrate NDC1 is a transmembrane nucleoporin required for NPC and nuclear envelope assembly. RNAi depletion in HeLa cells interferes with assembly of FG-repeat nucleoporins into NPCs. NDC1 interacts directly with Nup53 in vitro, suggesting it links the NE membrane to soluble nucleoporins to anchor the NPC in the membrane.\",\n      \"method\": \"RNAi knockdown, biochemical depletion in Xenopus in vitro NE assembly, in vitro binding assay (NDC1–Nup53 interaction)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi phenotype plus in vitro NE assembly plus direct binding assay, replicated across vertebrate systems and consistent with companion paper\",\n      \"pmids\": [\"16600873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human NDC1 (hNDC1) likely possesses six transmembrane segments and is located at the nuclear pore wall in mammals, frogs, insects, and nematodes. Depletion of hNDC1 from HeLa cells interferes with assembly of FG-repeat nucleoporins into NPCs. Loss of NDC1 function in C. elegans causes severe NPC defects and high larval/embryonic mortality, but homozygous NDC1-deficient worms can be propagated, indicating NDC1 is not absolutely essential.\",\n      \"method\": \"RNAi depletion, immunofluorescence, electron microscopy, C. elegans genetics\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods across multiple organisms, independent lab confirming companion study\",\n      \"pmids\": [\"16702233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The overall topology of Ndc1p is conserved from yeast to humans: six transmembrane segments in the N-terminal half, a large soluble C-terminal half (~300 aa) with the N- and C-termini exposed to the cytoplasm. Limited proteolysis of yeast Ndc1p in cellular membranes confirms the cytoplasmic orientation of its C-terminus. The human homologue (NET3/NDC1) contains three FG repeats in the C-terminus characteristic of nucleoporins.\",\n      \"method\": \"Limited proteolysis in cellular membranes, topology prediction, sequence analysis\",\n      \"journal\": \"The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — limited proteolysis experiment establishes C-terminal topology but performed in single lab with one method\",\n      \"pmids\": [\"16779818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Recruitment of vesicles containing the integral membrane nucleoporins POM121 and NDC1 to the forming nucleus depends on chromatin-bound ELYS/Nup107-160 complex, placing NDC1-containing vesicle recruitment downstream of ELYS and the Nup107-160 complex in the nuclear pore assembly pathway.\",\n      \"method\": \"Xenopus in vitro nuclear assembly, antibody inhibition, immunofluorescence, DNA-binding antibiotic competition assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution with inhibition experiments establishing pathway order, single lab\",\n      \"pmids\": [\"18596237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Yeast Ndc1 forms a distinct complex with transmembrane proteins Pom152 and Pom34, and two alternative complexes with soluble nucleoporins Nup53 and Nup59 (which in turn bind Nup170 and Nup157). Disruption of both groups of Ndc1 interactions causes defects in Ndc1 targeting and NPC structure with significant pore dilation. Depletion of Pom34 in cells lacking NUP53 and NUP59 blocks new NPC assembly.\",\n      \"method\": \"Co-immunoprecipitation, genetic double/triple mutant analysis, photoconvertible fluorescent protein fusions to track new NPC assembly, electron microscopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, genetic epistasis, live-imaging of NPC assembly, and EM structural analysis in one study\",\n      \"pmids\": [\"19414609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NDC1 is required for anchoring ALADIN at the NPC; siRNA depletion of NDC1 (but not GP210 or POM121) causes mislocalization of GFP-ALADIN. Conversely, depletion of ALADIN also leads to loss of NDC1 at the NPC. Direct association between NDC1 and ALADIN was demonstrated by FRET measurements.\",\n      \"method\": \"siRNA knockdown, GFP-ALADIN localization by fluorescence microscopy, FRET measurements\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with localization readout plus FRET for direct association, two orthogonal methods in single lab\",\n      \"pmids\": [\"19782045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"NDC1 directly interacts with nucleoporin ALADIN, and this interaction is required for targeting ALADIN to NPCs. NDC1 is also required for selective nuclear import.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with localization readout, nuclear import assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding shown by Co-IP, functional consequence demonstrated by siRNA, consistent with companion paper\",\n      \"pmids\": [\"19703420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Ndc1 physically interacts with the membrane-shaping proteins Rtn1 and Yop1 in yeast. Overexpression of NDC1 (but not other SPB insertion factors) rescues both SPB and NPC defects in rtn1Δ yop1Δ cells, suggesting Ndc1 is a common essential component competed for between NPC and SPB biogenesis pathways.\",\n      \"method\": \"Co-immunoprecipitation, genetic rescue by overexpression, electron microscopy, spindle orientation assay\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — physical interaction by Co-IP plus genetic rescue with pathway specificity, single lab\",\n      \"pmids\": [\"22798490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The interaction between Nup53 and the integral membrane protein Ndc1 is essential for vertebrate NPC assembly. The Ndc1-binding site on Nup53 overlaps with a membrane-bending region, and Ndc1 binding modulates Nup53's membrane-deforming activity. Nup53–Nup155 interaction is also critical for NPC formation as the main determinant of Nup155 recruitment to the assembling pore.\",\n      \"method\": \"In vitro binding assays, mutagenesis of Nup53 interaction domains, Xenopus in vitro NE assembly, depletion/rescue experiments\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding with mutagenesis, in vitro assembly reconstitution, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"24363447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A mutation in mouse Tmem48 (NDC1) causes gametogenesis defects with meiotic arrest at pachytene stage due to defective chromosome synapsis, and skeletal malformations with fused vertebrae and ribs. TMEM48 is specifically expressed in germ cells. Transgenic rescue with wild-type Tmem48 fully rescues phenotypes, confirming causality.\",\n      \"method\": \"Mouse genetics (positional cloning, whole exome sequencing), transgenic rescue, histology, immunocytochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — positional cloning with transgenic rescue establishing causality, multiple phenotypic readouts\",\n      \"pmids\": [\"24045954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Yeast Ndc1 interacts with the SUN domain-containing protein Mps3 at the nuclear envelope, as shown by fluorescence cross-correlation spectroscopy in live cells. The ndc1-L562S allele, unable to associate with Mps3, is lethal due to SPB duplication defects. Deletion of POM152 fully suppresses the growth and Mps3-binding defect of ndc1-L562S, suggesting Ndc1-Mps3 interaction controls distribution of Ndc1 between NPC and SPB.\",\n      \"method\": \"Fluorescence cross-correlation spectroscopy (FCCS) in live cells, genetic allele analysis, suppressor genetics\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FCCS for direct interaction in live cells plus genetic suppression analysis, single lab\",\n      \"pmids\": [\"24515347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NDC1 forms a complex with SEPTIN12 (SEPT12) in male germ cells. NDC1 overexpression restricts SEPT12 localization to the nucleus and represses SEPT12 filament formation. In sperm with mutated SEPT12, NDC1 disperses from the sperm neck to the manchette region and annulus. SEPT12-NDC1 complexes are required for normal spermiogenesis and sperm morphology.\",\n      \"method\": \"Co-immunoprecipitation, yeast 2-hybrid, immunofluorescence co-localization, overexpression experiments in germ cell lines, mouse knockout/knock-in models\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus yeast 2-hybrid for interaction, multiple functional readouts in mouse models, single lab\",\n      \"pmids\": [\"27854341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In C. elegans, Ndc1 determines NPC density at the reforming nuclear envelope. Loss of ndc1 results in faster turnover of the outer scaffold nucleoporin Nup160 at the NE (measured by FRAP-like photoconversion). NE formation fails in the absence of both Ndc1 and Nup53, indicating partially redundant roles. Upregulation of membrane synthesis restores nuclear growth after ndc1 loss but not after nup53 loss, demonstrating that membrane biogenesis can be decoupled from Ndc1-mediated NPC assembly.\",\n      \"method\": \"3D-EM tomography, photoconvertible fluorescent protein fusions for nucleoporin turnover, RNAi depletion, genetic double-mutant analysis, membrane synthesis manipulation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — EM tomography, live imaging with photoconversion, multiple genetic combinations, and orthogonal membrane manipulation in one rigorous study\",\n      \"pmids\": [\"35852146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ARRDC5 affects NDC1 localization during spermatogenesis by influencing SEC22A-mediated vesicle trafficking and transport of NDC1 and SUN5 to the head-tail coupling apparatus. In Arrdc5 knockout mice, sperm show bent-head defects and reduced motility due to failure of proper head-tail attachment.\",\n      \"method\": \"Mouse knockout model, mass spectrometry identification of NDC1 as ARRDC5 interactor, co-localization studies, intracytoplasmic sperm injection rescue\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mass spectrometry identification plus KO phenotype, but the mechanism specific to NDC1 function is inferred rather than directly tested\",\n      \"pmids\": [\"37997706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NDC1 activates PI3K/AKT signaling in hepatocellular carcinoma cells by interacting with BCAP31. Co-immunoprecipitation and mass spectrometry confirmed the NDC1–BCAP31 interaction.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, overexpression and knockdown in HCC cell lines, mouse xenograft\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/MS interaction without mechanistic dissection of how NDC1–BCAP31 activates PI3K/AKT, single lab\",\n      \"pmids\": [\"38348718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Biallelic NDC1 in-frame deletions or missense variants affecting amino acids required for ALADIN binding cause decreased recruitment of ALADIN to the nuclear envelope and decreased post-mitotic NPC insertion in patient-derived skin fibroblasts, resulting in polyneuropathy and a triple A-like syndrome without adrenal insufficiency.\",\n      \"method\": \"Diagnostic exome/RNA sequencing, skin fibroblast functional assays (ALADIN localization, NPC insertion assay), clinical correlation\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cell functional assays with direct NPC insertion measurement and ALADIN localization, consistent with prior mechanistic studies\",\n      \"pmids\": [\"39003500\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NDC1 (TMEM48/NET3) is a conserved integral membrane nucleoporin with six transmembrane segments whose cytoplasmic C-terminal domain interacts with multiple soluble nucleoporins (Nup53, Nup59, and ALADIN) and transmembrane proteins (Pom152, Pom34, Mps3, Rtn1/Yop1), anchoring nuclear pore complexes (and in yeast, spindle pole bodies) in the nuclear envelope by linking the NE membrane to the soluble NPC scaffold; its membrane-deforming partner Nup53 binding modulates membrane curvature during pore biogenesis, and it controls NPC density by stabilizing outer scaffold nucleoporins at the NE, with loss-of-function causing NPC assembly defects, gametogenesis failure, and (in humans) a triple A-like neuropathy via failure to recruit ALADIN to NPCs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NDC1 (TMEM48/NET3) is a conserved integral membrane nucleoporin that anchors nuclear pore complexes (NPCs) in the nuclear envelope by linking the NE membrane to the soluble NPC scaffold [#3, #4]. The protein adopts a conserved topology of six transmembrane segments in its N-terminal half and a large cytoplasmically exposed C-terminal domain that mediates its protein interactions [#5]. During NPC biogenesis, NDC1-containing membrane vesicles are recruited downstream of the chromatin-bound ELYS/Nup107-160 complex [#6], and NDC1 directly binds the soluble nucleoporin Nup53; because the Ndc1-binding site on Nup53 overlaps a membrane-bending region, this interaction modulates Nup53's membrane-deforming activity during pore formation and is essential for vertebrate NPC assembly [#3, #11]. In yeast, Ndc1 partitions among distinct assemblies—a transmembrane complex with Pom152 and Pom34 and alternative complexes with the soluble nucleoporins Nup53/Nup59—and disrupting both interaction groups mislocalizes Ndc1 and dilates pores [#7]. NDC1 sets NPC density by stabilizing outer-scaffold nucleoporins at the NE, acting partially redundantly with Nup53 in nuclear envelope formation; membrane biogenesis can be decoupled from Ndc1-dependent NPC assembly [#15]. NDC1 also recruits the nucleoporin ALADIN to the NPC through direct interaction, and the two depend on each other for NPC localization [#8, #9]. In yeast the same protein is required for insertion of the duplicating spindle pole body into the nuclear envelope, a function competed for with NPC biogenesis and governed by interactions with the membrane-shaping proteins Rtn1/Yop1 and the SUN-domain protein Mps3 [#0, #10, #13]. Loss-of-function disrupts gametogenesis: mouse Tmem48 mutation causes pachytene meiotic arrest from defective chromosome synapsis [#12], and NDC1 forms a germ-cell complex with SEPTIN12 required for normal spermiogenesis [#14]. In humans, biallelic NDC1 variants that impair ALADIN binding reduce ALADIN recruitment and post-mitotic NPC insertion, causing a triple A-like polyneuropathy syndrome [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established the founding function of Ndc1 by showing it is required for insertion of the duplicating spindle pole body into the nuclear envelope, defining an NE-resident factor acting in G1.\",\n      \"evidence\": \"EM, immunofluorescence, and genetic order-of-function analysis of temperature-sensitive ndc1 mutants in yeast\",\n      \"pmids\": [\"8349727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify molecular partners mediating SPB insertion\", \"Did not connect Ndc1 to NPC assembly\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed that NDC1 dosage is tightly constrained—both haploinsufficiency and overexpression disrupt SPB duplication—indicating it is a stoichiometry-sensitive component.\",\n      \"evidence\": \"Yeast genetic dosage experiments with flow cytometry and spindle morphology readouts\",\n      \"pmids\": [\"10468586\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking dosage to SPB defects not resolved\", \"Did not address NPC role\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended Ndc1 function beyond the SPB to NPC assembly, placing it in the NPC assembly pathway via nucleoporin incorporation and genetic interaction.\",\n      \"evidence\": \"Temperature-sensitive allele analysis, genetic epistasis with nic96-1, and nucleoporin incorporation assays in yeast\",\n      \"pmids\": [\"15075274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define direct binding partners\", \"Mechanism of nucleoporin incorporation unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined vertebrate NDC1 as a transmembrane nucleoporin required for NPC/NE assembly that links the NE membrane to soluble nucleoporins through a direct Nup53 interaction, and established conserved six-TM topology with a cytoplasmic C-terminus.\",\n      \"evidence\": \"RNAi in HeLa, Xenopus in vitro NE assembly, in vitro Nup53 binding, EM across multiple organisms, and limited proteolysis topology mapping\",\n      \"pmids\": [\"16600873\", \"16702233\", \"16779818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how Nup53 binding affects membrane shape\", \"C. elegans data showed it is not absolutely essential, leaving redundancy unexplained\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Ordered NDC1 vesicle recruitment within the assembly pathway, showing it depends on chromatin-bound ELYS/Nup107-160.\",\n      \"evidence\": \"Xenopus in vitro nuclear assembly with antibody inhibition and DNA-binding competition assays\",\n      \"pmids\": [\"18596237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the receptor coupling vesicles to the ELYS complex\", \"Co-recruited POM121 vs NDC1 roles not separated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapped Ndc1 into discrete interaction modules—transmembrane (Pom152/Pom34) and soluble nucleoporin (Nup53/Nup59)—required for targeting and pore integrity, and identified ALADIN as an NDC1-dependent NPC partner.\",\n      \"evidence\": \"Reciprocal co-IP, genetic double/triple mutants, photoconvertible NPC-assembly imaging and EM in yeast; siRNA, FRET and co-IP for NDC1-ALADIN in human cells\",\n      \"pmids\": [\"19414609\", \"19782045\", \"19703420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of module partitioning not resolved\", \"How ALADIN recruitment relates to NPC scaffold assembly unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified Ndc1 as a limiting factor shared between NPC and SPB biogenesis through interaction with membrane-shaping Rtn1/Yop1.\",\n      \"evidence\": \"Co-IP, genetic rescue by NDC1 overexpression, EM, and spindle orientation assays in yeast\",\n      \"pmids\": [\"22798490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not quantify the competitive partitioning mechanism\", \"Specificity of Rtn1/Yop1 effects on each pathway unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established the molecular logic of NDC1-Nup53 coupling—Ndc1 binds a Nup53 membrane-bending region and modulates its membrane-deforming activity—and showed Tmem48 mutation causes gametogenesis and skeletal defects in mouse with rescue confirming causality.\",\n      \"evidence\": \"In vitro binding with Nup53 mutagenesis and Xenopus NE assembly; mouse positional cloning/exome sequencing with transgenic rescue and histology\",\n      \"pmids\": [\"24363447\", \"24045954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural details of curvature modulation not resolved\", \"Mechanism linking NPC defects to synapsis failure not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed an Ndc1-Mps3 (SUN-domain) interaction at the NE governs distribution of Ndc1 between NPC and SPB, with Pom152 deletion suppressing the binding-deficient allele.\",\n      \"evidence\": \"Fluorescence cross-correlation spectroscopy in live yeast, allele analysis, and suppressor genetics\",\n      \"pmids\": [\"24515347\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve how partitioning is regulated through the cell cycle\", \"Direct Mps3-binding interface not mapped structurally\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified an NDC1-SEPTIN12 germ-cell complex controlling SEPT12 localization and required for normal spermiogenesis, extending NDC1's roles into sperm morphogenesis.\",\n      \"evidence\": \"Co-IP, yeast two-hybrid, immunofluorescence, overexpression in germ cell lines, and mouse knockout/knock-in models\",\n      \"pmids\": [\"27854341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SEPT12 interaction is NPC-related or independent unresolved\", \"Direct binding interface not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined NDC1 as a determinant of NPC density that stabilizes outer-scaffold nucleoporins and acts partially redundantly with Nup53, and decoupled membrane biogenesis from Ndc1-mediated NPC assembly.\",\n      \"evidence\": \"3D-EM tomography, photoconversion nucleoporin turnover, RNAi, double-mutant analysis and membrane-synthesis manipulation in C. elegans\",\n      \"pmids\": [\"35852146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of scaffold stabilization not resolved\", \"How redundancy with Nup53 is partitioned mechanistically unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked NDC1 to human disease by showing biallelic variants impairing ALADIN binding reduce ALADIN recruitment and post-mitotic NPC insertion, causing a triple A-like polyneuropathy.\",\n      \"evidence\": \"Diagnostic exome/RNA sequencing and patient-derived fibroblast functional assays for ALADIN localization and NPC insertion\",\n      \"pmids\": [\"39003500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tissue-specificity of the neuropathy phenotype not explained\", \"Why adrenal insufficiency is absent unlike classical triple A unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NDC1's NE/NPC scaffolding function relates to its reported roles in cancer signaling (BCAP31/PI3K-AKT) and to vesicle-trafficking factors (ARRDC5/SEC22A) in spermatogenesis remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"NDC1-BCAP31 mechanism activating PI3K/AKT not dissected\", \"ARRDC5/SEC22A link to NDC1 inferred rather than directly tested\", \"No structural model of the full NDC1 interactome\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 4, 5, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 8, 9, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 4, 5, 15]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:1852241\", \"supporting_discovery_ids\": [3, 7, 15]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [9, 18]}\n    ],\n    \"complexes\": [\"NPC (nuclear pore complex)\", \"spindle pole body (yeast)\", \"Ndc1-Pom152-Pom34 complex\", \"NDC1-SEPTIN12 complex\"],\n    \"partners\": [\"NUP53\", \"ALADIN\", \"POM152\", \"POM34\", \"RTN1\", \"MPS3\", \"SEPT12\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":9,"faith_total":9,"faith_pct":100.0}}